Cocaine abuse remains a significant problem in our society with total annul cost of over $100 billion. It is clear that effective therapies are needed to assist addicted individuals in achieving abstinence, however, currently no effective pharmacotherapies are available. The studies described in this research proposal involve the design, synthesis and in vitro characterization of novel polypharmacophoric single entity, treatments for cocaine abuse. The basic premise is that for the treatment of cocaine abuse, a pharmacological agent able to treat anhedonia and craving (pharmacological agonist), and to prevent some of the behavioral effects of cocaine by acting (behavioral antagonism) in the event of recidivism would provide an effective treatment stratagem. To achieve this goal we will rationally design and optimize proprietary 4- arylpiperidines as single entities that exhibit significant inhibitory activity at the dopamine and serotonin transporters (pharmacological agonists of cocaine to treat anhedonia and craving respectively) and also exhibit significant 5-HT2A antagonist activity (behavioral antagonism of cocaine). This research exploits the extensive structure activity relationships available in the literature for structurally related analogs at the monoamine transporters and the 5-HT2A receptors. PROPOSED COMMERCIAL APPLICATIONS: Currently there are no effective treatments for the treatment of cocaine addiction. The successful completion of the work proposed here should ultimately lead to the development and marketing of a pharmacotherapy for the treatment of cocaine abuse. Additionally, the compounds prepared may prove useful for the treatment of other neurologically relevant disorders such as attention deficit hyperactivity disorder (ADHD), depression, obsessive compulsive disorder and related behavioral disorders.